1000 Titel
  • Structural Insights Into Thyroid Hormone Transport Mechanisms of the L-Type Amino Acid Transporter 2
1000 Autor/in
  1. Hinz, Katrin M. |
  2. Meyer, Katja |
  3. Kinne, Anita |
  4. Schülein, Ralf |
  5. Köhrle, Josef |
  6. Krause, Gerd |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-06-01
1000 Erschienen in
1000 Quellenangabe
  • 29(6): 933-942
1000 FRL-Sammlung
1000 Verlagsversion
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414734/ |
  • https://doi.org/10.1210/me.2015-1044 |
1000 Ergänzendes Material
  • https://academic.oup.com/mend/article-lookup/doi/10.1210/me.2015-1044#supplementary-data |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Thyroid hormones (THs) are transported across cell membranes by different transmembrane transporter proteins. In previous studies, we showed marked 3,3′-diiodothyronine (3,3′-T2) but moderate T3 uptake by the L-type amino acid transporter 2 (Lat2). We have now studied the structure-function relationships of this transporter and TH-like molecules. Our Lat2 homology model is based on 2 crystal structures of the homologous 12-transmembrane helix transporters arginine/agmatine antiporter and amino acid/polyamine/organocation transporter. Model-driven mutagenesis of residues lining an extracellular recognition site and a TH-traversing channel identified 9 sensitive residues. Using Xenopus laevis oocytes as expression system, we found that side chain shortening (N51S, N133S, N248S, and Y130A) expanded the channel and increased 3,3′-T2 transport. Side chain enlargements (T140F, Y130R, and I137M) decreased 3,3′-T2 uptake, indicating channel obstructions. The opposite results with mutations maintaining (F242W) or impairing (F242V) uptake suggest that F242 may have a gating function. Competitive inhibition studies of 14 TH-like compounds revealed that recognition by Lat2 requires amino and carboxylic acid groups. The size of the adjacent hydrophobic group is restricted. Bulky substituents in positions 3 and 5 of the tyrosine ring are allowed. The phenolic ring may be enlarged, provided that the whole molecule is flexible enough to fit into the distinctly shaped TH-traversing channel of Lat2. Taken together, the next Lat2 features were identified 1) TH recognition site; 2) TH-traversing channel in the center of Lat2; and 3) switch site that potentially facilitates intracellular substrate release. Together with identified substrate features, these data help to elucidate the molecular mechanisms and role of Lat2 in T2 transport.
1000 Sacherschließung
lokal xenopus laevis
lokal hydrophobicity
lokal ion channel gating
lokal carrier proteins
lokal thyroid hormone transport
lokal membrane transport proteins
lokal carboxylic acids
lokal amino acid transporter
lokal arginine
lokal crystal structure
lokal molecule
lokal amino acids
lokal oocytes
lokal phenylalanine
lokal antiporter
lokal diiodothyronines
lokal agmatine
lokal polyamines
lokal mutation
lokal mutagenesis
lokal helix (snails)
lokal thyroid hormones
lokal tyrosine
lokal cell membrane
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/SGlueiwgS2F0cmluIE0u|https://frl.publisso.de/adhoc/creator/TWV5ZXIsIEthdGph|https://frl.publisso.de/adhoc/creator/S2lubmUsIEFuaXRh|https://frl.publisso.de/adhoc/creator/U2Now7xsZWluLCBSYWxm|https://frl.publisso.de/adhoc/creator/S8O2aHJsZSwgSm9zZWY=|https://frl.publisso.de/adhoc/creator/S3JhdXNlLCBHZXJk
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
1000 Fördernummer
  1. Ki1751/1-1; Ko-922/17-1; Kr1273/5-1
1000 Förderprogramm
  1. SPP Thyroid Trans Act 1629
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm SPP Thyroid Trans Act 1629
    1000 Fördernummer Ki1751/1-1; Ko-922/17-1; Kr1273/5-1
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6402745.rdf
1000 Erstellt am 2017-06-02T10:11:11.164+0200
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1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Fri Oct 21 11:36:24 CEST 2022
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1000 Vgl. frl:6402745
1000 Oai Id
  1. oai:frl.publisso.de:frl:6402745 |
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